NGGT006 Gene Therapy for Homozygous Familial Hypercholesterolemia

Early Phase 1RecruitingNCT06125847

First Affiliated Hospital Xi'an Jiaotong University21 enrolled

Overview

This is an early phase 1, open-label, single-center, dose-escalation, pilot trial to evaluate the safety and efficacy of an intravenous infusion of NGGT006 in homozygous familial hypercholesterolemia (HoFH) patients with LDLR mutations. NGGT006 is an adeno-associated viral (AAV) vector carrying codon-optimized human LDLR gene, driving the expression of LDLR protein with normal function and promoting the clearance of low-density lipoprotein cholesterol (LDL-C).

Homozygous familial hypercholesterolemia (HoFH) is a rare inherited disorder of lipoprotein metabolism, characterized by extreme elevations in low-density lipoprotein cholesterol (LDL-C) and leading to early onset of severe coronary artery disease. This is an early phase 1, open-label, single-center, dose-escalation, pilot trial to evaluate the safety and efficacy of a single intravenous infusion of NGGT006 in HoFH patients with LDLR mutations. NGGT006 is an adeno-associated viral (AAV) vector carrying codon-optimized human LDLR gene, driving the expression of LDLR protein with normal function and promoting the clearance of low-density lipoprotein cholesterol (LDL-C). 4-21 subjects will be enrolled and divided into 4 groups according to the principle of dose escalation, respectively administered intravenous infusion of NGGT006 at dose group 1 (7.5e12vg/kg), dose group 2 (1.5e13vg/kg) , dose group 3 (3e13vg/kg) and dose group 4 (4e13vg/kg). The researcher is allowed to extend 0-9 patients. All subjects will undergo 52 weeks of treatment observation and further 260 weeks of long-term follow-up.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Eligibility

Sex: ALLMin age: 12 YearsMax age: 55 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Voluntarily sign informed consent form; * Male or female, 12 ≤ age ≤ 55 years (first patient≥ 18 years), diagnosed as homozygous familial hypercholesterolemia with genetic confirmation of two mutant alleles of the LDL receptor (LDLR) gene; * AAV8 neutralizing antibodies can be negative or reduced to negative levels through methods such as plasma exchange or IgG-degrading enzymes. * Untreated LDL-C ≥10 mmol/L (386mg/ dL) or treated LDL-C ≥7 mmol/L (270mg/ dL) together with cutaneous or tendon xanthoma before age 18 years; * Had been on stable medication for ≥30 days if receiving lipid-lowering therapy (or ≥60 days if receiving alirocumab or evolocumab) prior to screening and not scheduled for addition of new drugs or dose adjustments during the study; * Agreed to follow a low-fat diet and comply with all study procedures, including dietary requirements, study visits, fasting blood draws, and the study treatment regimen.; * Agreed to maintain a similar exercise volume and intensity to baseline during the study period; * Agreed to maintain good lifestyle habits; * No history of alcohol abuse or alcohol dependence (diagnosed as F10 in ICD-10 code); * No sexual activity for 14 days prior to administration and negative serum pregnancy test in female participants; * Participants of childbearing potential agreed to use highly effective contraception for at least 365 days from administration of NGGT006; * No plan of stent implantation within 3 months. Exclusion Criteria: * Positive for hepatitis B surface antigen, hepatitis C, human immunodeficiency virus (HIV) or syphilis test; * Clinically significant abnormalities in liver function test: alanine aminotransferase (ALT) \>3 × upper limit of normal (ULN) and/or aspartate aminotransferase (AST) \>3 × ULN; * Baseline blood pressure \>160/100 mmHg (1 repeat measurement is allowed); * Uncontrolled myocardial infarction or heart failure, or had surgery plan within 1 year; * Diabetes diagnosed within 3 months or with poor control (HbA1c \>9%); * Acute or chronic kidney failure; * Hemoglobin (Hb) \<120g/L (male), Hb \<110 (female); * Platelet test results deemed clinically significantly abnormal by the investigator; * History or laboratory tests suggestive of thrombosis; * Had contraindications to glucocorticoid (e.g., epilepsy, severe schizophrenia, active peptic ulcer); * Life expectancy less than 1 year; * With malignant tumors; * Liver fibrosis or liver cancer; * Previous gene therapy treatment; * Hypersensitivity to any excipient of the AAV product (including trehalose) or cortisone or immunosuppressants (sirolimus, rituximab, tacrolimus); * Participation in any other clinical trial within 3 months; * History of stent implantation within 1 month or myocardial infarction within 3 months; * Breastfeeding females; * Any other condition that may not be appropriate for the study in the opinion of the Investigator.

Outcomes

Primary Outcomes

Incidence of treatment-related adverse events (AE) and serious adverse events (SAE)

Incidence of AE and SAE, as assessed by physical examinations, clinical laboratory parameters and adverse event reporting

Time frame: 52 weeks

Absolute change and percent change in LDL-C

Change in LDL-C concentration from baseline to week 52

Time frame: 52 weeks